The Geriatric Dementia Research Clinic will continue integrated studies of patients, of brain, and of extranueral tissues, in Alzheimer disease and other dementias. The overall hypothesis being tested is that in a significant subgroup of patients, Alzheimer's disease is a genetic disorder with systemic manifestations which can usefully be studied in non-neural tissues as well as in brain. The core will continue to supply meticulously evaluated patients and tissues for study, including autopsy brain; it will also provide biopsy brain ("neurosurgical waste"), tissue cultures (including cells from large kindreds), antibodies, and statistical, computer, and administrative support. Metabolic studies will define the already documented abnormalities in cellular calcium homeostasis in relation to cell physiological events over msec to min, using new spectrofluorometric technology. The site(s) of demonstrated deficiencies in cellular oxidative metabolism will be defined with radiochemical and other probes, including oxygen electrode measurements. Molecular biological studies will test whether the deficiencies in thiamine pyrophosphate (TPP) dependent enzymes demonstrated in Alzheimer brain reflect abnormalities in structure or transcription of the respective genes, at least in strata of patients. Immunocytochemical and in situ hybridization studies will test the possibility that selective vulnerability of n. basalis cells in Alzheimer's disease may relate to their demonstrated relative enrichment in at least one of the deficient TPP- dependent enzymes. Pilot therapeutic trials will test the value in Alzheimer's disease of agents suggested by our experimental studies: 3,4-diaminopyridine and high dose thiamine. (The latter led to a statistically although not clinically significant improvement in cognition in these patients in a preliminary study).